Carboxyl-terminal binding protein (CtBP) was originally identified based on its ability to bind the carboxyl terminus of the E1A oncoprotein (Boyd et al., 1993; Schaeper et al., 1995). Subsequently, CtBP was found to be a transcriptional co-repressor interacting with DNA-binding transcription factors (Chinnadurai, 2002). Unlike most transcription factors with consensus DNA binding sites, CtBP indirectly binds DNA via various DNA binding partners at multiple DNA sequences, thus its transcriptional repression is context-specific. CtBP has remarkable amino acid homology with NADH-dependent dehydrogenases. Cancer cells typically have more NADH due to both hypoxia and pseudo-hypoxia (NADH production when oxygen concentration is not limited) (Sattler et al., 2007; Yeng et al., 2008; Zhang et al., 2007). The inventors have found NADH binds to CtBP with high affinity (Kd −100 nM), which, without being tied to any particular theory, presumably causes a conformational change in CtBP that favors its binding to transcriptional factors (e.g., transcriptional repressors) (Zhang et al., 2002). The inventors have elucidated the major pathways controlled by CtBP in cancer cells and found CtBP directly represses epithelial genes and pro-apoptotic genes independently of p53, thus increasing cancer cell survival and migration.
CtBP interacts with E1A and many of its transcriptional factor partners through a conserved sequence motif, Pro-X-Asp-Leu-Ser (PXDLS) (Schaeper et al., 1995). A 14 mer E1A peptide (SEQ ID NO: 1) inhibited the CtBP/E1A interaction in vitro with an IC50 of approximately 7 μM (Zhang et al. 2000).
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